I cover cardiology news for CardioExchange, a social media website for cardiologists published by the New England Journal of Medicine. I was the editor of TheHeart.Org from its inception in 1999 until December 2008. Following the purchase of TheHeart.Org by WebMD in 2005, I became the editorial director of WebMD professional news, encompassing TheHeart.Org and Medscape Medical News. Prior to joining TheHeart.Org, I was a freelance medical journalist and wrote for a wide variety of medical and computer publications. In 1994-1995 I was a Knight Science Journalism Fellow at MIT. I have a PhD in English from SUNY Buffalo, and I drove a taxicab in New York City before embarking on a career in medical journalism. You can follow me on Twitter at: @cardiobrief.

HPS2-THRIVE: No Benefit, Signal Of Harm For Niacin Therapy

The largest-ever study of niacin has failed to show a clinical benefit for niacin and even found a strong signal of harm. Merckannounced today that the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study did not meet its primary endpoint. In that study, the combination of a statin and Merck’s niacin compound, Tredaptive, a combination of extended-release niacin and laropiprant, an anti-flushing agent, was compared to statin therapy alone in 25,673 patients at high risk for cardiovascular events.

After a median followup of 3.9 years, the combination of niacin and laropiprant ”did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy,” according to Merck. Even more troubling, the company reported that there was “a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.”

Merck said it was now no longer planning to seek approval of Tredaptive in the United States. The drug’s initial application for approval in the US was rejected in 2008. HPS2-THRIVE was designed to answer criticism from the FDA and other experts about the lack of any evidence demonstrating clinical benefit.

Tredaptive (also known as Cordaptive in some places) is approved in some countries outside the US. Merck said it is “recommending that providers not start new patients” on the drug. It is unclear whether the drug will remain on the market in these places.

Although niacin, a natural vitamin, has been used for decades to raise HDL, a clinical benefit has never been demonstrated. In 2011 the NIH’s AIM-HIGH trial found no benefit for extended-release niacin. Critics said the trial was underpowered and otherwise flawed. HPS2-THRIVE, most agreed, would provide a more definitive test of the effect of niacin.

HPS2-THRIVE adds to the string of failures associated with trials of HDL-related therapies, although some hope remains for CETP inhibitors, despite the failure of two large clinical trials. It appears likely that the results of HPS2-THRIVE will also impact the use of existing niacin products. Bernstein analyst Timothy Anderson said it may “cause some collateral damage to AbbVie’s Niaspan.”

Responding to the breaking news, Steve Nissen said he had three initial thoughts about the trial:

What were the “non-fatal serious adverse events” that showed a statistically significant increase?

Also don’t forget that this trial did not have a cut-off for HDL, so that patients could have any level of HDL and still get into this trial, not just patients with low HDL where presumptively the greatest benefit would be seen, according to the HDL-raising hypothesis. We will need to see how this sub-group responded, which was a pre-specified sub-group analysis. As far as the vague “excess of non-fatal serious adverse events”, it is no surprise given the known issues with the use of niacin, such as flushing (even occasionally to the point of causing vasodilation resulting in rare syncope), hyperuricemia, gout and gout flares, peptic ulcer disease, and hyperglycemia. If these non-fatal adverse events were higher int the niacin-laropriprant arm, I would not be at all surprised. If, however, we saw an excess of non-fatal strokes, as a tendency was seen in AIM-HIGH, that would be much more concerning. Obviously science and medical care cannot and should not be based on lay press reports and we need to see and digest all the data from this trial when it comes out. Stay by your radios (and Internet feeds), my friends!

Update #2: James Stein sent the following comment:

HPS did not THRIVE! I am disappointed. It suggests that in people on a statin with well controlled LDL and non-HDL cholesterol levels, adding niacin may not reduce CVD risk. I still think niacin is a useful drug for those who can’t reach goals on statins or who can’t take them, and for selected patients with combined dyslipidemia. However, this may be as much about laropiprant as it is about niacin. I am especially concerned about the increase in non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. You may recall that the idea for using laropiprant was to improve the tolerability of niacin by blocking flushing. However a close look at the laropiprant data for its effectiveness as a flushing blocker showed that at the dose it was being used at, it was not significantly better than adult dose aspirin.

More worrisome, pre-clinical Merck research showed an off-target effect of laropiprant on platelet DP1 receptors. Bleeding times were not prolonged, so the meaning of this off-target effect is unclear, but this is evidence that the drug may affect more than just the DP1 receptor on dermal blood vessels. We know DP1 receptors also are on neurons and lung tissue, among other places. We in the lipid world need to be very humble about off target effects – even if we can’t explain them with our current knowledge base.

WHITEHOUSE STATION, N.J., December 20, 2012 – Merck (NYSE:MRK), known outside the United States and
Canada as MSD, today announced that the HPS2-THRIVE (
Heart
Protection
Study 2-
Treatment of
HDL to
Reduce the
Incidence of
Vascular
Events) study of TREDAPTIVE
™(extended-release niacin/laropiprant) did not meet its primary endpoint. Merck and the investigators are informing regulatory agencies of these results. The company is also preparing communications to health care providers in countries where the medicine is currently available, and will continue to work with regulators to provide updated information to health care providers. Based on the current understanding of these new data and until further analyses can be completed, Merck is recommending that providers not start new patients on TREDAPTIVE. Merck does not plan to seek regulatory approval for the medicine in the United States.

HPS2-THRIVE was independently conducted by the Clinical Trial Service Unit at Oxford University and funded by Merck. The study enrolled 25,673 patients considered to be at high risk for cardiovascular events. Of those enrolled, 14,741 were from Europe (the United Kingdom and Scandinavia) and 10,932were from
China. Patients in the study were followed for a median of 3.9 years. HPS2-THRIVE compared extended -release niacin and laropiprant plus statin therapy versus statin therapy. It was not designed to assess directly the separate effects of either extended-release niacin or laropiprant.

In the study, adding the combination of extended-release niacin and laropiprant to statin therapy did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy. In addition, there was a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.

With the agreement of the independent research team at Oxford University, Merck is sharing results from the study with regulatory agencies in countrieswhere the medicine is approved (under the brand names TREDAPTIVE or CORDAPTIVE) and in other countries as well. The investigators are conducting additional analyses, including regional analyses, to further understand the results. They anticipate reporting the detailed study results in the first quarter of 2013.

”While we are disappointed in these results, we thank the investigators who have conducted the study and the patients who have participated in it,” saidPeter S. Kim, Ph.D., president, Merck Research Laboratories. “We are committed to working closely with the independent research team at Oxford University and with regulatory agencies to understand the results and determine next steps.”

About TREDAPTIVE/CORDAPTIVE

TREDAPTIVE/CORDAPTIVE has been approved in approximately 70 countries, including in Europe, and is sold in approximately 40 countries. TREDAPTIVE is also sold under the brand names PELZONT in Italy and TREVACLYN in Italy and Portugal. Sales through the first three quarters of 2012 were approximately $13 million.

AboutMerck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching

policies, programs and partnerships. For more information, visit
www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (
www.sec.gov).

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Based on accumulating evidence of failed niacin and other HDL-raising trials (eg, torcetrapib, etc), I am not ready to ditch the HDL hypothesis in its entirety. But not all HDL is created equal. It is not enough to just raise levels of “HDL,” so the particular form of HDL (particle “species”) needs to be considered. Framingham and other epidemiologic trials, as well as molecular and clinical experiments, have established a protective role for HDL, but it’s a far more complex story than originally imagined. Consider for example the case of ApoA-1 Milano, a variant of the apolipoprotein moiety of HDL found in a proportion of the population of a small village in northern Italy. There is a low prevalence of heart disease among people with the variant form even though they have low levels of HDL. Their variant form appears to be very protective against cardiovascular disease. Without knowing anything else about HDL, one could have studied them and come to the conclusion that a LOW level of HDL was a good thing. Red herrings abound. How to raise the right kind of HDL will be the big question going forward in HDL research.

Historically, as done by its major practitioners – the physicians who follow ideas from orthomolecular medicine – the best form of niacin to take is regular-release niacin. It is well known that extended-release niacin increases the risk of adverse effects for the patient – including liver damage. Regular release niacin does not damage the liver. Orthomolecular medicine has shown for several tens of thousands of patients that niacin is safe at doses far above the 2000 mg a day used for cholesterol problems – the standard dose is 3000 mg a day with increases to 6000-9000 mg or even more a day for mental health problems.

Certainly, like the flawed studies on estrogen replacement – where the progestin additive increased the risk for heart attacks and cancer – the HPS2-THRIVE study adds statins and laropiprant to niacin – which increases the risk tremendously for patients. The study should have used regular-release niacin alone in one of the study groups for comparison to the combinations.